Water → (S)-2-(3-chloro-2-hydroxypropyl)isoindoline-1,3-dione

S-epichlorohydrin (III, 98.9% enantiomerically pure, 99.3 chemical % purity, 4.9605 g, 53.61 mmol) is added to a slurry of potassium phthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) and phthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and the mixture stirred at 50° for 4.5 hrs. The mixture is added to methylene chloride (50 ml) and water (50 ml) added. The solids are removed by filtration with reduced pressure and washed with methylene chloride (20 ml). The phases are separated in the filtrate and the aqueous washed with methylene chloride (50 ml). The combined organics were washed with water (50 ml) and the aqueous backextraceted with methylene chloride (50 ml) after adding water (25 ml). The combined organics are dried over sodium sulfate and saturated with hydrogen chloride gas at 6°. Water (100 ml) is added and the phases separated. The aqueous phase is washed with methylene chloride (2×50 ml) and the combined organic phases are dried over sodium sulfate. The organic phase is concentrated under reduced pressure and toluene added (77 ml). The mixture is concentrated under reduced pressure to 31 g net weight and toluene (50 ml) and heptane (75 ml) added. The solids are filtered off and washed with toluene/heptane (1/1, 20 ml). The filtrate is concentrated under reduced pressure to 17 g net weight, heptane (100 ml) added and the mixture concentrated under reduced pressure to 15 g net weight. Heptane (100 ml) and methylene chloride (100 ml) is added and the mixture concentrated under reduced pressure to 130 g net weight. The solids are filtered off and washed with heptane/methylene chloride (2/1, 3×15 ml). The filtrate is concentrated under reduced pressure to 11 g net weight and toluene (90 ml) then heptane (400 ml) added. The resultant slurry is then cooled to −20° and the product collected by filtration under reduced pressure, washed with heptane and dried to give a crude solid. Flash chromatography of the crude solid (silica gel; eluting with a gradient of 15-45% ethyl acetate/cyclohexane) gives the title compound as an analytical sample, NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20, 7.70-7.76 and 7.82-7.88 δ; CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65 δ; MS (CI, NH3), M/Z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240 (0.31), 221 (100); [α]25D=−33 (C=0.712, CHCl3). NMR of the mosher ester derivative showed the product to have an enantiomeric purity of 96.2% upon comparison to the NMR of the mosher ester of the racemate.

1. additionadded
2. customThe solids are removed by filtration with reduced pressure
3. washwashed with methylene chloride (20 ml)
4. customThe phases are separated in the filtrate
5. washthe aqueous washed with methylene chloride (50 ml)
6. washThe combined organics were washed with water (50 ml)
7. additionafter adding water (25 ml)
8. dry with materialThe combined organics are dried over sodium sulfate and saturated with hydrogen chloride gas at 6°
9. additionWater (100 ml) is added
10. customthe phases separated
11. washThe aqueous phase is washed with methylene chloride (2×50 ml)
12. dry with materialthe combined organic phases are dried over sodium sulfate
13. concentrationThe organic phase is concentrated under reduced pressure and toluene
14. additionadded (77 ml)
15. concentrationThe mixture is concentrated under reduced pressure to 31 g net weight and toluene (50 ml) and heptane (75 ml)
16. additionadded
17. filtrationThe solids are filtered off
18. washwashed with toluene/heptane (1/1, 20 ml)
19. concentrationThe filtrate is concentrated under reduced pressure to 17 g net weight, heptane (100 ml)
20. additionadded
21. concentrationthe mixture concentrated under reduced pressure to 15 g net weight
22. additionHeptane (100 ml) and methylene chloride (100 ml) is added
23. concentrationthe mixture concentrated under reduced pressure to 130 g net weight
24. filtrationThe solids are filtered off
25. washwashed with heptane/methylene chloride (2/1, 3×15 ml)
26. concentrationThe filtrate is concentrated under reduced pressure to 11 g net weight and toluene (90 ml)
27. additionheptane (400 ml) added
28. temperatureThe resultant slurry is then cooled to −20°
29. filtrationthe product collected by filtration under reduced pressure
30. washwashed with heptane
31. customdried
32. customto give a crude solid
33. washeluting with a gradient of 15-45% ethyl acetate/cyclohexane)

ORD record

ord-19699c3da5074a4e8c058dce85aeca03

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06362334B1